This invention relates to a novel use of imidazole compounds in the treatment of CNS injuries.
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cells.
Dinareilo, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to IL-8, such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
There remains a need for the treatment, and for the prevention of CNS injuries which are related to the ability of compounds which are cytokine suppressive, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
This invention relates to the use of CSAID(trademark) cytokine suppressive binding compounds, or pharmaceutical compositions thereof in the treatment of CNS injuries, such as head trauma, and ischemia.
The preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) as noted herein. The preferred method of inhibition is the inhibition of the CSBP/p38/RK kinase pathway.
The present invention is to the novel use of a cytokine inhibitor, in particular that of cytokine CSBP/p38, for treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, various CNS injuries. A preferred group of these cytokine suppressive compounds are described herein as compounds of Formula (I).
CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel. The role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
TNF-xcex1 is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated herein by reference.
Models of closed head injuries and treatment with mixed 5-LO/CO agents is discussed in Shohami et al., J. of Vaisc and Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp 99-107 (1992) whose disclosure is incorporated herein by reference. Treatment which reduced edema formation was found to improve functional outcome in those animals treated.
Compounds for use herein include the cytokine inhibitors as described in U.S. Ser. No. 08/091,491, published as WO95/02575; WO96/21452; U.S. Ser. Nos. 08/369,964; 08/473,396; 08/659,102; 08/764,003; WO96/40143; U.S. Ser. No. 08/473,398; WO96/21654; WO93/14081; U.S. Ser. No. 08/095,234; WO95/03297; U.S. Ser. No. 08/481,671; PCT/US97/00619; PCT/US97/00614; PCT/US97/00500; PCT/US97/00529; U.S. Ser. Nos. 60/013,357; 60/013,358; 60/013,359; WO93/14082: WO95/13067; and WO95/31451. Each of these references are incorporated by reference herein in their entirety.
Preferred compounds for use as cytokine inhibitors are those compounds of Formula (I) noted below. Synthetic chemistry and methods of pharmaceutical formulations thereof are also contained within each noted patent application. A description of the assay for inhibition of the cytokine specific binding protein (CSBP) is also found in WO95/07922, whose disclosure is incorporated by reference in its entirety.
Accordingly, the present invention provides for use of a compound of Formula (I): 
wherein:
R1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, which heteroaryl ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb;
Y is X1-Ra;
X1 is oxygen or sulfur;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, xe2x80x94C(Z)NR7R17, xe2x80x94C(Z)OR16, xe2x80x94(CR10R20)vCOR12, xe2x80x94SR5, xe2x80x94SOR5, xe2x80x94OR12, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R12, xe2x80x94NR10C(Z)R16, or xe2x80x94(CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, xe2x80x94C(Z)NR13R14, xe2x80x94C(Z)OR3, xe2x80x94(CR10 R20)mxe2x80x3COR3, xe2x80x94S(O)mR3, xe2x80x94OR3, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)mxe2x80x3NR10C(Z)R3, xe2x80x94NR10S(O)mxe2x80x2R8, xe2x80x94NR10S(O)mxe2x80x2NR7R17, xe2x80x94ZC(Z)R3 or xe2x80x94(CR10R20)mxe2x80x3NR13R14;
v is 0, or an integer having a value of 1 or 2;
m is 0, or the integer 1 or 2;
mxe2x80x2 is an integer having a value of 1 or 2,
mxe2x80x3 is 0, or an integer having a value of 1 to 5;
R2 is C1-10 alkyl N3, xe2x80x94(CR10R20)nxe2x80x2 OR9, heterocyclyl, heterocyclylC1-10 alkyl, C1-10alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14, (CR10R20)nNO2, (CR10R20)nCN, (CR10R20)nxe2x80x2SO2R18, (CR10R20)nS(O)mxe2x80x2NR13R14, (CR10R20)nC(Z)R11, (CR10R20) nOC(Z)R11, (CR10R20)nC(Z)OR11, (CR10R20)nC(Z)NR13R14, (CR10R20)nC(Z)NR11OR9, (CR10R20)nNR10C(Z)R11, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)NR13R14, (CR10R20)nN(OR6)C(Z)R11, (CR10R20)nC(xe2x95x90NOR6)R11, (CR10R20)nNR10C(xe2x95x90NR19)NR13R14, (CR10R20)nOC(Z)NR13R14, (CR10R20)nNR10C(Z)NR13R14, (CR10R20)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;
n is an integer having a value of 1 to 10;
nxe2x80x2 is 0, or an integer having a value of 1 to 10;
Z is oxygen or sulfur,
Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocycylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted;
Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 akyl;
R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties xe2x80x94SR5 being xe2x80x94SNR7R17 and xe2x80x94SOR5 being xe2x80x94SOH;
R6 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclic, aroyl, or C1-10 alkanoyl;
R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR5;
R8 is C1-10 alkyl, halo-substitutcd C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
R9 is hydrogen, xe2x80x94C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl;
R12 is hydrogen or R16;
R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
R15 is R10 or C(Z)xe2x80x94C1-4 alkyl;
R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl;
R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl;
R19 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
or a pharmaceutically acceptable salt thereof.
Suitably, R1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl. Preferably, R1 is an optionally substituted 4-pyridyl or 4-pyrimindyl, more preferably an optionally substituted 4-pyrimidinyl.
The R1 heteroaryl ring may be optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb.
Suitably Y is X1-Ra wherein X1 is oxygen or sulfur, preferably oxygen.
Preferably the hetoaryl ring R1 is substituted by alkoxy, alkylthio, amino, methylamino, NHRa, or Y. More preferably, Y, NHRa, or C1-4 alkoxy. A preferred ring placement of the R1 substituent on the 4-pyridyl derivative is the 2-position, such as 2-methoxy-4-pyridyl. A preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy-pyrimidinyl.
Suitably, Ra is C1-6 alkyl, aryl, arylC1-6 alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted.
Suitably, Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl.
When the substituent is Y, and Ra is aryl, it is preferably phenyl or naphthyl. When Ra is aryl alkyl, it is preferably benzyl or napthylmethyl. When Ra is heterocyclic or heterocyclic alkyl moiety, the heterocyclic portion is preferably pyrrolindinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothipyran-sulfinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl. It is noted that the heterocyclic rings herein may contain unsaturation, such as in a tryptamine ring.
These Ra aryl, heterocyclic and heteroaryl rings may also be optionally substituted one or more times independently with halogen; C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted C1-4 alkyl; C1-4 alkoxy, such as methoxy or ethoxy; S(O)m alkyl and S(O)m aryl (wherein m is 0, 1, or 2); C(O)OR11, such as C(O)C1-4 alkyl or C(O)OH moieties; C(O)R11; xe2x80x94OC(O)Rc; Oxe2x80x94(CH2)s-Oxe2x80x94, such as in a ketal or dioxyalkylene bridge; amino; mono- and di-C1-6 alkylsubstituted amino; xe2x80x94N(R10)C(O)Rb; xe2x80x94C(O)NR10R20; cyano, nitro, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; optionally subtituted aryl, such as phenyl; an optionally substituted arylalkyl, such as benzyl or phenethyl; aryloxy, such as phenoxy; or arylalkyloxy such as benzyloxy; these aryl and arylalkyl moieties may be substituted with halogen, alkyl, alkoxy, S(O) m alkyl, amino, or mono- and di-C1-6 alkylsubstituted amino.
Suitably Rc is optionally substituted C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl moieties.
Preferably, the Ra groups include benzyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, morpholinopropyl, piperonyl, piperidin-4-yl, alkyl substituted piperidine, such as 1-methyl piperidine, or 2,2,6,6-tetramethylpiperidin-4-yl.
Preferably, when the substituent is NHRa then Ra is aryl, arylalkyl, halosubstituted arylalkyl, halosubstituted aryl, heterocyclic alkyl, hydroxy alkyl, alkyl-1-piperidinecarboxylate, heterocyclic, alkyl substituted heterocyclic, halosubstituted heterocyclic, or aryl substituted heterocyclic. More specifically Ra is benzyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl, 2-hydroxy ethyl, ethyl-1-peperidinecarboxylate, piperonyl, piperidin-4-yl, alkyl substituted piperidine, chlorotryptamine, and tetrathiohydropyranyl.
Preferably, when the R1 optionally substituent is a substituted C1-4 alkoxy or C1-4 alkylthio, the alkyl chain is substituted by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethoxy; C1-10 alkoxy, such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2; amino, mono and di-substituted amino, such as in the NR7R17 group, i.e. tert-butylaminoethoxy; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; or halosubstituted C1-10 alkyl, such as CF3. Preferably, such R1 substituents are tertbutylaminoethoxy, or hydroxyethoxy.
Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety. More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or substituted at the 3-position with fluoro, chloro, C1-4 alkoxy, methane-sulfonamido or acetamido, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro or fluoro, more preferably chloro. Most preferably, R4 is 4-fluorophenyl.
In Formula (I), Z is suitably oxygen or sulfur.
Suitably, R2 is selected from C1-10 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-10 alkyl, (CR10R20)nNS(O)2R18, (CR10R20)nS(O)mR18, arylC1-10 alkyl, (CR10R20)nNR13R14, optionally substituted C3-7cycloalkyl, or optionally substituted C3-7cycloalkyl C1-10 alkyl. Preferably R2 is morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, 4-aminopiperidine, 4amino-2,2,6,6-tetramethyl piperidine, 4-hydroxycyclohexyl, 4-methyl-4-hydroxy cyclohexyl, 4-pyrrolinindyl-cyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-keto cyclohexyl, 4-oxiranyl, or 4-hydroxy-4-propynyl)cyclohexyl.
Preferably R2 is an optionally substituted heterocyclyl ring, and optionally substituted heterocyclylC1-10 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted C3-7cycloalkyl, an optionally substituted C3-7cycloalkyl C1-10 alkyl, (CR10R20)nC(Z)OR11 group, (CR10R20)nNR13R14, (CRR20)nNHS(O)2R18, (CR10R20)nS(O)mR18, an optionally substituted aryl; an optionally substituted arylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nC(Z)R11, or (CR10R20)nC (xe2x95x90NOR6)R11 group.
More preferably R2 is an optionally substituted heterocyclyl ring, and optionally substituted heterocyclylC1-10 alkyl, an optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloallyl C1-10 alkyl.
More preferably R2 is an optionally substituted C4 or C6 cycloalkyl; morpholinyl butyl; morpholinyl propyl; morpholinyl ethyl; cyclohexyl substituted by methyl, phenyl, benzyl, amino, acetamide, aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, hydroxy, nitroethyl, pyrrolidinyl, ethynyl, 1-propynyl, xe2x95x90O, Oxe2x80x94(CH2)2Oxe2x80x94, xe2x95x90NOR11, wherein R11 is hydrogen, alkyl or aryl, NHOH, or N(OH)xe2x80x94C(Oxe2x80x94NH2; aminopropyl; piperidinyl; N-benzyl-4-piperidinyl; N-methyl-4-piperidinyl; 2,2,6,6-tetramethypiperidinyl; substituted piperidine, such as 1-Formyl-4-piperidine; or a 1-ethoxycarbonyl-4-piperidine.
When R2 is an optionally substituted heterocyclyl, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted, the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; C1-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzyl and wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the definition section below); C(O)OR11, such as the C(O)C1-4 alkyl or C(O)OH moieties; C(O)H; C(O)C1-4 alkyl, hydroxy substituted C1-4 alkyl, C1-4 alkoxy, S(O)mC1-4 alkyl (wherein m is 0, 1, or 2), NR10R20 (wherein R10 and R20 are independently hydrogen or C1-4alkyl).
Preferably if the ring is a piperidine, the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a 1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4-position, it is preferably substituted in the 2- or 6-position or both, such as 2,2,6,6-tetramethyl-4-piperidine. Similarly, if the ring is a pyrrole, the ring is attached to the imidazole at the 3-position, and the substituents are all directly on the available nitrogen.
When R2 is an optionally substituted heterocyclyl C1-10 alkyl group, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. Preferably this alkyl moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties. The heterocyclic ring herein is also optionally substituted in a similar manner to that indicated above for the direct attachment of the heterocyclyl.
When R2 is an optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl C1-10 alkyl, the cycloalkyl group is preferably a C4 or C6 ring, most preferably a C6 ring, which ring is optionally substituted. The cycloalkyl ring may be optionally substituted one to three times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; S(O)m aryl; cyano, nitro, amino, mono and di-substituted amino, such as in the NR7R17 group, wherein R7 and R17 are as defined in Formula (I), or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR15 (and R15 is as defined for Formula (I)); N(R10)C(O)Xxe2x80x21 (wherein R10 is as defined for Formula (I)), and Xxe2x80x21 is C1-4 alkyl, aryl or arylC1-4alkyl); N(R10)C(O) aryl; C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; optionally substituted alkyl wherein the substituents are halogen, (such as CF3), hydroxy, nitro, cyano, amino, mono and di-substituted amino, such as in the NR7R17 group, S(O)m alkyl and S(O)m aryl, wherein m is 0, 1 or 2; optionally substituted alkylene, such as ethylene or propylene; optionally substituted alkyne, such as ethyne; C(O)OR11 (wherein R11 is as defined in Formula (I)), such as the free acid or methyl ester derivative; the group Re; xe2x80x94C(O)H; xe2x95x90O; xe2x95x90Nxe2x80x94OR11; xe2x80x94N(H)xe2x80x94OH (or substituted alkyl or aryl derivatives thereof on the nitrogen or the oxime moiety); xe2x80x94N(ORd)xe2x80x94C(O)xe2x80x94R6xe2x80x2; an optionally substituted aryl, such as phenyl; an optionally substituted arylC1-4alkyl, such as benzyl of phenethyl; an optionally substituted heterocycle or heterocyclic C1-4alkyl, and further these aryl, arylalkyl, heterocyclic, and heterocyclic alkyl moieties are optionally substituted one to two times by halogen, hydroxy, C1-10 alkoxy, S(O)m alkyl, cyano, nitro, amino, mono and di-substituted amino, such as in the NR7R17 group, an alkyl, halosubstituted alkyl.
Suitably Rd is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1-10 alkanoyl group.
Suitably Re is a 1,3-dioxyalkylene group of the formula xe2x80x94Oxe2x80x94(CH2)s-Oxe2x80x94, wherein s is 1 to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety, or ketal functionality.
Suitably R6xe2x80x2 is NR19xe2x80x2R20; alkyl1-6; halosubstituted alkyl1-6; hydroxy substituted alkyl1-6; alkenyl2-6; aryl or heteroaryl optionally substituted by halogen, alkyl1-6, halosubstituted alkyl1-6, hydroxyl, or alkoxy1-6.
Suitably R19 xe2x80x2 is H or alkyl1-6.
Suitably R20xe2x80x2 is H, alkyl1-6, aryl, benzyl, heteroaryl, alkyl substituted by halogen or hydroxyl, or phenyl substituted by a member selected from the group consisting of halo, cyano, alkyl1-12, alkoxy1-6, halosubstituted alkyl1-6, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R19xe2x80x2 and R20xe2x80x2 may together with the nitrogen to which they are attached form a ring having 5 to 7 members, which members mnay be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen. The ring may be saturated or contain more than one unsaturated bond. Preferably R6xe2x80x2 is NR19xe2x80x2R20xe2x80x2 and R19xe2x80x2 and R20xe2x80x2 are preferably hydrogen.
When the R2 cycloalkyl moiety is substituted by NR7R17 group, or NR7R17 C1-10 alkyl group, and the R7 and R17 are as defined in Formula (I), the substituent is preferably an amino, amino alkyl, or an optionally substituted pyrrolidinyl moiety.
A preferred ring placement on the cycloalkyl moiety is the 4-position, such as in a C6 ring. When the cycloalkyl ring is di-substituted it is preferably di-substituted at the 4 position, such as in: 
wherein R1xe2x80x2 and R2xe2x80x2 are independently the optional substituents indicated above for R2. Preferably, R1xe2x80x2 and R2xe2x80x2 are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkyne, aryl, arylalkyl, NR7R17, and N(R10)C(O)R11. Suitably, alkyl is C1-4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; aryl such as in phenyl; arylalkyl, such as in benzyl; optionally substituted alkyne, such as ethyne or propynyl; or together R1xe2x80x2 and R2xe2x80x2 are a keto functionality.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in OR3, or for certain R2 moieties.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d, unless specifically defined, shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C1-10alkyl; C1-10 alkoxy, such as methoxy ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C1-10 alkyl, such CF3; halosubstituted C1-10 alkoxy; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C1-10 alkoxy; S(O)m alkyl; amino, mono and di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9d or xe2x80x9chalogensxe2x80x9d, include the halogens: chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, ethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.
The term xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclylalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydro pyran, or imidazolidine.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety as also defined herein unless otherwise indicated.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S (O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
xe2x80x9caroylxe2x80x9dxe2x80x94a C(O)Ar, wherein Ar is a phenyl, naphthyl, or aryl alkyl derivative such as defined above, such groups include but are not limited to benzyl and phenethyl.
xe2x80x9calkanoylxe2x80x9dxe2x80x94a C(O)C1-10 alklo wherein the alkyl is as defined above.
For the purposes herein the xe2x80x9ccorexe2x80x9d 4-pyrimidinyl moiety for R1 is referred to 
as the formula:
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
Exemplified compounds of Formula (I) include:
1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Methylsulfonamidopropyl)-4-(4-fuorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(N-Phenylmethyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(N-Phenylmethyl-N-methyl)aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(1-Pyrrolidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Diethylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(1-Piperidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(Methylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[2-(4-Morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazol;
1-[3-(4-Morpholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
(+/xe2x88x92)-1-[3-(4-Morpholinyl)propyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylsulfinylphenyl)-5-(4-pynidyl)imidazole;
1-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[4-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(Methylthio)phenyl]-4-fluorophenyl)-5-(4-pyridyl)imidazole;
(+/xe2x88x92)-1-[3-(Methylsulfinyl)phenyl]-4-(4-fluoropherpyl)-5-(4-pyridyl)imidazole;
1-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[2-(Methylsulfinyl)pheny]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[4-(4-Morpholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridy)imidazole;
1-tert-Butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(2,2-Diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Hydroxyiminylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-Cyanomethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(4-Morpholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;
4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-chloropyridin-4-yl)imidazole;
4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-anino-4-pyridinyl)imidazole;
1-(4-Carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(4-Carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(3-Carboxy)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;
1-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-[3-(4-Morpholinyl)propyl]imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpiperidin-4-yl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2-propyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(cyclopropylmethyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-carboxyethyl-4-piperidinyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;
1-Methyl-4-phenyl-5-(pyridyl)imidazole;
1-Methyl-4-[3-(chlorophenyl)]-5-[4-pyridinyl]imidazole;
1-Methyl-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
(+/xe2x88x92)-1-Methyl-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
(+/xe2x88x92)-4-(Fluorophenyl)-1-[3-(methylsulfinyl)propyl]-5-(4-pyridinyl)imidazole;
4-(4-Fluorophenyl)-1-[(3-methysulfonyl)propyl]-5-(4-pyrdinyl)imidazole;
1-(3-Phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-[3-(Phenylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinoly)imidazole;
(+/xe2x88x92)-1-(3-Phenylsulfinylpropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-(3-Ethoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-(3-Phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-[3-(4-Morpholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole;
1-[3-(4-Morpholinyl)propyl]-4-(3,4-dichlorophenyl)-5-(4-pyridyl)imidazole;
4-[4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole;
4-(4-Fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;
(+/xe2x88x92)-4-(4-Fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;
(E)-1-(1-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
1-(2-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
5-[(2-N,N-Dimethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]imidazole;
1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)phenyl]imidazole;
1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]imidazole;
1-(Cyclopropylmethyl)-4-(3,4dichlorophenyl)-5-(4-pyridinyl)imidazole;
1-(Cyclopropylmethyl)-4-(3-trifluoromethylphenyl)-5-(4-pyridinyl)imidazole;
1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;
1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoromethylphenyl)imidazole;
5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxy-2,2-dimethylethyl)imidazole;
1-(1-Formyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;
1-(2,2-Dimethyl-3-morpholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-Amino-4-pyrimidinyl)imidazole;
4-(4-Fluorophonyl)-5-(4-pyridyl)-1-(2-acetoxyethyl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpyrrolin-3-yl)imidazole;
5-(2-Aminopyrimidin-4-yl)-4-fluorophenyl)-1-(2,2,6,6-tetramethypiperidin-4-yl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;
5-[(2-Ethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
4-(4-Fluorophenyl)-5-[2-(isopropyl)aminopyrimidiny-4-yl]-1-(1-methylpiperdin-4-yl)imidazole;
5-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;
5-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;
5-[4-(2-N-Methylthio)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;
4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole;
4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;
1-tert-Butyl-4-(4-fluorophenyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;
5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazole;
5-[4-(2-N-Methylamino-4-pyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetra-methyl-4-piperidine)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-thiopyranyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-pyranyl)imidazole;
5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2-cyanoethyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfinylpyranyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfonylpyranyl)imidazole;
5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl-4-piperidinyl)imidazole;
5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(trifluoroacetyl-4-piperdinyl)imidazole;
5-(4-Pyridyl)-4-(fluorophenyl)-1-(4-piperidinyl)imidazole;
5-(4-Pyridyl)-4-(4-fluorophenyl)-1-(1-t-butoxy carbonyl-4-piperidinyl)imidazole;
5-(2-amnino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-(1,3-dioxycyclopentyl)cyclohexyl)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-ketocyclohexyl)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-cyclohexyl oxime)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-cyclohexyl hydroxylamino)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(trans-4-hydroxyurea)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(cis-4-hydroxyurea)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-ketocyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(trans-4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(cis-4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-(cis-pyrrolidinyl)cyclohexyl]imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-(trans-1-pyrrolidinyl)cyclohexyl]imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-ethynyl-4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-(1-propynyl)-4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-amino-4-methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4acetamido-4-methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-oxiranylcyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-cyanomethyl-4-hydroxycyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-hydroxymethylcyclohexly)imidazole;
5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-hydroxy-4-(1-propynyl)cyclohexyl]imidazole;
5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-isopropylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimnidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-phenylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-benzylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-cyanomethylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-cyanoethyl)cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-aminoethyl)cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-nitroethyl)cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxymethyl-4-aminocyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-aminocyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrmdinyl]-4-(4-fluorophenyl)-1-(4-aminocyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-thiomethylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimdinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-hydroxy methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-aminomethylcyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4amino-4-methylcyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-methylcyclohexyl)imidazole;
5-[4-(2-amino)pyrimdinyl]-4-(4-fluorophenyl)-1-(4-oxiranyl-cyclohexyl)imidazole;
4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;
4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylio-4-pyrimidinyl)imidazole;
5-[(2-Benzylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
4-(4-Fluorophenyl)-1-(1-methylpiperdin-4-yl)-5-[2-(4-tetrahydrothiopyranyl)aminopyrimidin-4-yl]imidazole;
4-(4-Fluorophenyl)-5-[(2-hydroxy)ethylamino]pyrimidiny-4-yl-1-(1-methyl-piperdin-4yl)imidazole;
5-[(2-(3-Chlorobenzylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methyl-iperdin-4-yl)imidazole;
5-[(2-(1-Naphthylmethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
5-[(2-(1-Benzyl-4-piperidinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
4-(4-Fluorophenyl)-1-(1-methylpiperdin-4-yl)-5-[2-[3-(morpholino)propyl]aminopyrimidiny-4-yl]imidazole;
5-[2[(3-Bromophenyl)amino]pyrimidin-4-yl)]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
5-[(2(Piperonylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperidin-4-yl)imidazole;
5-[(2-(4-Piperdinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
5-[(2-(5-Chlorotryptamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
5-[(2-(2,2,6,6-tetramethylpiperidin-4-yl)aminopyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
5-[(2-[(1-Ethoxycarbonyl)piperdin-4-yl]aminopyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;
1-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;
cis-1-(Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;
trans-1-(4-Hydroxycyclohexyl)-4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;
1-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methyltio)pyrimidin-4-yl]imidazole;
trans-1-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methylthio)pyrimidin-4-yl]imidazole;
1-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-hydroxy)pyrimidin-4-yl]imidazole;
1-(4-Oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-isopropoxy)pyrimidin-4-yl]imidazole;
1-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-isopropoxy)pyrimidin-4-yl]imidazole;
trans-1-(4-Hydroxy-4-methylcyclohexyl)-4-(4-fuorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;
cis-1-(4-Hydroxy-4-methylcyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole;
trans-1-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-ethoxy)pyrimidine-4-yl]imidazole;
1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole;
1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyridinyl)imidazole;
1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)-4-pyridinyl]imidazole;
1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)-4-pyridinyl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-methoxyphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]-imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-aminocarbonylphenoxy)pyrimidin-4-yl]-imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-ethylphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-benzyloxyphenoxy)pyrimidin-4-yl]-imidazole;
1-(Piperidin-4-yl)-4-(4-fluoraphenyl)-5-[2-(4-cyanophenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-hydroxyphenoxy)pyrimidin-4-yl]imidazole;
1-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenoxy)pyridin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(fluorophenyl)-5-[2-(4-methylphenoxy)pyridin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-chorophenoxy)pyridin-4-yl]imidazole;
1-[3-(N-Morpholino)propyl]-4-(4-fluorophenyl)-5-[2-(phenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophonyl)-5-[2-(3-methoxyphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenylphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-phenoxyphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-hydroxyphenoxy)pyrimidin-4-yl]imidazole;
1-(3-(N-Morpholino)propyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-hydroxyphenoxy)pyrimidin-4yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-((3,4-methylenedioxy)phenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-fluorophenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-fluorophenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(2-methoxyphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3-trifluoromethylphenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(3,4-difluorophenoxy)pyrimidin-4-yl]imidazole;
1-(Piperidin-4-yl)-4-(4-(fluorophenyl)-5-[2-(4-methylsulfonylphenoxy)pyrimidin-4-yl]imidazole;
1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-thiophenoxypyrimidin-4-yl)imidazole,
1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(1-methyltetrazol-5-ylthio)pyridin-4-yl]imidazole;
5-[2-(2-Hydroxyethoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole;
5-[2-(2-Hydroxyethoxy)]pyrimidin-4-yl)-4-(4-fluorophenyl)-1-(hydroxy cyclohexyl)imidazole;
5-[2-(2-tert-Butylamino)ethoxypyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole;
5-[2-(2-tert-Butylamino)ethoxypyrimidin-4-yl]-4-(4-fluorophenyl)-1-(4-hydroxycyclohexyl)imidazole;
1-(4-Piperidinyl)-4-(4-Flourophenyl)-5-(2-isopropoxy-4-pyrimidinyl)imidazole;
1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole;
5-(2-Hydroxy-4-pyrimidinyl)-4-(4-fluorophenyl)-4-(4-piperidinyl)imidazole;
5-(2-Methoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;
5-(2-iso-Propoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;
5-(2-Methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;
5-(2-Methylthio-4-pyrimidinyl)-4-(4-fluorophenyl-1-[(1-methyl-4-piperidinyl]imidazole;
5-(2-Ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;
1-(1-Ethylcarboxylpiperidin-4-yl)-3-(4-thiomethylphenyl)-5-[2-(thiomethyl)pyrimidin-4-yl]-imidazole;
1-(1-Ethylcarbonylpiperidine-4-yl)-4-(4-methylsulfinylphenyl)-5-[2-methylsulfinylpyrimidin-4-yl]imidazole;
or pharmaceutically acceptable salts thereof.
Methods of Treatment
The compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mrnamal, which is exacerbated or caused by a neurotramatic event, such as closed head injuries.
Compounds of Formula (I) are capable of inhibiting proinflamnnatory cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use in therapy. IL-1, IL6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
Accordingly, the present invention provides for method of treating a neurotraumatic disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a CSAID(trademark) cytokine suppresive compound, wherein the compound is an inhibitor of CSBP/p38/RK kinase. Preferably, the cytokine inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
The discovery that the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1, IL-6, IL-8 and TNF, and CNSP/p38 is based upon the effects of the compounds of Formulas (I) on the production of the IL-1, IL-8 and TNF in in vitro assays which are described herein, or based upon the kinase or binding assay for CBSP as also described herein.
As used herein, the term xe2x80x9cinhibiting the production of IL-1 (IL-6, IL-8 or TNF)xe2x80x9d refers to:
a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels;
c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or
d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or subnormal levels.
As used herein, the term xe2x80x9ccytokine interferingxe2x80x9d or xe2x80x9ccytokine suppressive amountxe2x80x9d refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
A new member of the MAP kinase family, alternatively termed CSBP, p38, or RK, has been identified, See Lee et al., Nature, Vol. 300 n(72), 739-746 (1994). Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. The cytokine biosynthesis inhibitors, of the present invention, compounds of Formula (I), have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors we of aid in determining the signaling pathways involvement in inflammatory responses.
In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be Formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
Compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100xc2x0 C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Compounds of Formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral admininstration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15 mg. The daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15 mg/kg. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.